Among the diseases widely called as adult diseases or life-style related diseases, those such as abnormal carbohydrate/lipid metabolisms, impaired glucose tolerance/diabetes/hyperlipemia/high-blood pressure related thereto, and abdominal obesity form clusters of the diseases, and are recognized as syndromes such as metabolic syndromes and insulin resistance syndromes, or visceral steatosis, syndrome X and the like. Patients with these syndromes not only have a low quality of life but also have higher lethal risk or a risk of developing fatal vascular disorders such as arterial sclerosis as compared with healthy people. Compounds having a thiazolidine structure such as rosiglitazone and pioglitazone, which have been recently found as antidiabetic agents, have a strong effect of improving insulin resistance and are expected to be applied to the treatment of the above syndromes in addition to diabetes (Non-patent Literature 1). The mechanism of these compounds having a thiazolidine structure is the agonist activity to PPAR-γ that is a transcription factor, and other compounds without a thiazolidine structure are also found as PPAR-γ agonists. PPAR-γ agonists or antagonists are expected to be applied to the diseases relating to insulin resistance or metabolic syndromes, for example, prevention/treatment of metabolic diseases, e.g. diabetes, gestational diabetes mellitus and polycystic ovary syndrome; prevention/treatment of cardiovascular diseases, e.g. ischemic heart disease, myocardial infarction, angina pectoris, and coronary artery cardiovascular disease; prevention/treatment of liver diseases, e.g. non-alcoholic/nonviral steatohepatitis and fatty liver disease (NASH and NAFLD); and prevention/treatment of malignant neoplasm and cancers such as large bowel cancer. Further, it has been reported that PPAR-γ agonists have a direct anti-atherogenic action and an immunoregulatory activity via immunocompetent cells such as monocytes.
On the other hand, since PPAR-γ agonists have unfavorable side-effects such as edema and weight gain, it is desired to develop PPAR-γ agonists without such side-effects. Meanwhile, fibrate agents such as clofibrate, fenofibrate and bezafibrate are antihyperlipemic agents and have the agonistic action to PPAR-α that is a transcription factor. Though it is known that PPAR-α agonists other than fibrate agents also have the antihyperlipemic action, they hardly have the antihyperglycemic action. Thus, PPAR-α agonists having a strong antihyperglycemic action are desired as therapeutic agents of a wide range of metabolic diseases such as metabolic syndromes. As mentioned above, it is obvious that the compounds that have the interaction with PPAR-α or PPAR-γ are useful. In addition to it, the agents that have the interactions with both PPAR-α and PPAR-γ can be expected to be useful for the wider range of patients since such agents have both the antihyperlipemic action due to their action to PPAR-α and the antidiabetic action due to their action to PPAR-γ (Non-patent Literature 2). Further, it is thinkable that the weight gain due to the PPAR-γ action is diminished by the effect of promoting the use of in vivo lipids due to the PPAR-α action. Dual agonists of PPAR-α and PPAR-γ have not been placed on the market in Japan. In other countries, low molecular compounds reported as having the dual agonistic action, such as muraglitazar, tesaglitazar, ragaglitazar, TAK-559 and GW-1536, have been clinically examined. However, the development of ragaglitazar, TAK-559 and GW-1536 was suspended because of the problems in the safety tests on animals. Though the effect of the dual agonists has been clinically examined, all of the problems seen in PPAR-γ agonists such as edema and weight gain have not been improved (Non-patent Literature 3). Thus, it is thought that the dual agonists still have the problems to be improved on safety thereof. Therefore, at present, it is desired to develop PPAR activity regulators such as PPAR-α agonists, PPAR-γ agonists and PPAR-α, γ dual agonists, which have good medicinal effects and high safety.
[Non-patent Literature 1] Evans R. M. et al.: PPARs and the complex journey to obesity. Nature Medicine 10 p 1-7, 2004.
[Non-patent Literature 2]1 Henke B. R.: Peroxisome proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes. J Med Chem 47 p 4118-4127, 2004.
[Non-patent Literature 3] Skrumsager B. K. et al.: Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes.: J Clin Pharmacol 43 p 1244-56, 2003.